Molecular Origins of Parkinson’s Disease May Lead To Treatment Options In Huntington’s Disease

Researchers from The Rockefeller University, New York, in collaboration with Columbia University, New York, have recently released results from a study in which they identified the molecular changes that results in the loss of neurons in Parkinson’s disease (PD); a discovery that may have significant implications in discovering future therapeutic options for other neurodegenerative diseases such as Huntington’s disease (HD). The study, entitled, “Identification of neurodegenerative factors using translatome–regulatory network analysis” was published in the latest edition of Nature: Neuroscience.

To understand why certain neurons in the brain of PD patients are prone to succumb to premature cellular death, the investigators utilized an experimental mouse model of PD to assess what were the key determinants of neuronal survival and death. Their findings showed there are two gene-regulating molecules that appear to have a protective effect in the set of neurons most affected by the disease. When their activity wanes, neuronal death occurs and disease sets in.

In a University press release, Dr. Paul Greengard, PhD, Paul Greengard, Vincent Astor Professor, head of Laboratory of Molecular and Cellular Neuroscience, RU, and senior study author, stated, “Within a dying nerve cell, the levels of hundreds of proteins change. Some of these shifts are consequences, others are causes. We set out to find which cause cell death among neurons. Using a new combination of techniques, we identified two of these so-called master regulatory molecules — a discovery that offers an unexpected explanation as to why one population of neurons degenerates in Parkinson’s, while similar neighbors do not suffer from the same degree of degeneration.”

Dr. Greengard, continued, “In an unexpected contradiction to current models, the proteins we found protect the SNpc. Because dopamine and its metabolites can be toxic, we can speculate that, in the course of evolution, SATB1 and ZDHHC2 arose to protect this particular set of sensitive neurons from cell death. The discovery of these two molecules’ role in Parkinson’s may assist in the development of treatments, because they are potential new targets for drugs.”

Dr. Greengard’s lab team member, senior research associate  and lead study author, Lars Brichta, shared his enthusiasm for the results and stated, “Conventional gene activity profiling approaches would not have been able to identify SATB1 and ZDHHC2 as key protective factors because the levels of these proteins do not change. But even though they continue to be expressed within the neurons, it appears that their regulatory activity drops off and they no longer stimulate their target genes. We later found similar changes in activity in the brains of Parkinson’s patients, particularly those in the early stages.”

Dr. Greengard and his team foresee these findings may be useful to undesrtand other neurodegenerative diseases such as HD, possible allowing the creation of new and effective therapies to treat these debilitating conditions.